Colorectal cancer (CRC) is the third most common tumor type and a leading cause of cancer death in both men and women. Despite improved prognosis for colorectal cancer patients in the last decade, it still causes considerable morbidity and mortality and survival rates lag behind those of breast and prostate cancer patients.
Causes of CRC are believed to be a result of interactions between inherited and environmental factors. The primary risk factor of CRC is age as 90% of the cases are diagnosed over the age of 50 years. Other reported risks include, among others, familial history of adenomatous polyposis, people suffering from inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, diabetes, physical inactivity, obesity, smoking, high alcohol intake and a diet rich in animal fat.
In most cases, CRCs develop slowly over a period of several years. Symptoms of colon cancer do not appear in all patients when the disease is in an early stage but only after it has advanced in gravity. Most CRCs begin as a polyp, a growth of tissue that starts in the lining and grows into the center of the colon or rectum. There are several types of polyps: adenomas, which can become cancerous but are easily removed during a colonoscopy; inflammatory polyps which appear after ulcerative colitis and can also become cancerous and hyperplastic polyps which rarely transform into cancer. 95% of colorectal cancers are adenocarcinomas.
Colorectal cancer has distinct stages and the most commonly used staging system for colorectal cancer is that of the American Joint Committee on Cancer (AJCC), sometimes also known as the TNM system. Older staging systems for colorectal cancer include the Dukes and Astler-Coller systems. The stage describes to what extent the cancer has spread in the body: how far the cancer has grown into the wall of the intestine (primary tumor status, “T”), whether or not it has spread to the lymph nodes (nodal status, “N”), and whether or not it has reached nearby structures (metastatic status, “M”). According to TNM status, patients are assigned one of four stages: I, II, III or IV. The stage of a cancer is one of the most important factors in determining prognosis and treatment options. Each stage has different treatment options. Treatment of cancer is curative when diagnosed at early stage but prognosis is poorer at later stages.
Surgery is the preferred treatment approach for early-stage colorectal cancer, allowing patients to make a full recovery. Standard regimens in the first and second-line treatment settings are selected from “XELOX” (Capecitabine and oxaliplatin), “FOLFIRI” (5-fluorouracil, leucovirin and irinotecan) and “FOLFOX” (5-fluorouracil, leucovirin and oxaliplatin). However, while adjuvant chemotherapy (a combination of fluoropyrimidines such as capecitabine with oxaliplatin or irinotecan) has been shown to extend survival in stage IIb (advanced and metastatic stage), clinical benefit in early stages of the disease remains unclear. The emergence of antibody therapies such as AVASTIN (bevacizumab, Genentech/Roche/Chugai), ERBITUX (cetuximab, Eli Lilly/Merck KGaA/Bristol-Myers Squibb) and VECTIBIX (panitumumab, Amgen), respectively targeting the vascular endothelial growth factor (VEGF) or the epidermal growth factor (EGFR) for colorectal cancer management, has helped to improve patient prognosis further.
The Wnt pathway is instrumental in orchestrating proper tissue development in embryos and normal tissue maintenance in adults. This is achieved by directing a specific set of genes that are responsible for the control of cell growth, movement and survival. It has been found that chronic activation of the Wnt pathway in intestinal epithelial cells drives their expansion into benign adenomas (also known as polyps), which frequently progress to invasive colon carcinoma following additional genetic mutations facilitating their progression into malignant, invasive and metastatic cancers (Barker and Clevers, 2006, Nature Reviews Drug Discovery, 5, 997-1014; Polakis, 2000, GenesDev, 14, 1837-1851). A range of other cancers also present signs of aberrant Wnt signaling activity but clear mutations in key Wnt signaling components have been identified with less frequency than in colon cancer. It is believed that abnormal activation of the various genes resulting from aberrant activation of the Wnt pathway may promote uncontrolled cell growth and survival, and consequently may also drive cancer formation and growth in a broad range of tissues, including breast, skin and brain. Aberrant Wnt signaling is also implicated in other conditions such as rheumatoid arthritis, neurological disorders and bone diseases (Barker and Clevers, 2006, supra).
Macrocyclic lactones are fermentation products, or chemical derivatives thereof, of microorganisms such as those belonging to the genus Streptomyces, classified in two groups: Avermectins (including ivermectin, abamectin, doramectin, eprinomectin, and selamectin), derived from Streptomyces avermitilis and Milbemycins (including milbemycin oxime and moxidectin), derived from Streptomyces hygroscopicus or Streptomyces cyanogriseus. 
The family of Avermectins covers closely related compounds and semi-synthetic mixtures thereof (Albers-Schönberg et al., 1981, J. Am. Chem. Soc., 103, 4216-4221). They have been described as antiparasitic agents, particularly active against nematodes and arthropods. Avermectins have found wide application as pesticides and antiparasitic agents for human and animal use (e.g. cattle, sheep, horses) (Burg et al., 1979, Antimicrob. Agents Chemother., 15, 361-367). Among Avermectins, Abamectin and one of its synthetic derivatives, Ivermectin, are the most extensively used compounds. Abamectin is used to control insect and mite pests in agriculture and fire ants. Abamectin is also used as a veterinary anthelmintic. Ivermectin is used for the treatment of the parasitic infections strongyloidiasis and onchocerciasis (river blindness) in humans and other worm infestations (e.g., ascariasis, trichuriasis and enterobiasis) and is commercialized under the name of MECTIZAN/STROMECTOL (Merck & Co. Inc.) for oral treatment of onchocerciasis caused by Onchocerca volvulus. Ivermectin has been recently described as presenting anti-leukemic activity in acute myeloid leukemia (AML) cell lines (Sharmeen et al., 2010, Blood, Vol. 116(18), 3593-3603).
The family of Milbemycins exhibit structures that are related to Avermectins' structures (Albers-Schönberg et al., 1981, above; Mishima et al., 1974, Abstract papers, 18th Symp. Chem. Natural Products, 309-316, Kyoto, October 17-19; Mishima et al., 1975, Tetrahydron Lett., 711-714; Okazaki et al., 1983, J. Antibiotics, 36, 438-441). As Avermectins, the family of Milbemycins covers closely related compounds and semisynthetic mixtures thereof are known to have insecticidal, acaricidal and anthelmintic activities (U.S. Pat. No. 4,144,352).
Despite advances in chemotherapy, the majority of patients with advanced tumors eventually succumb to their disease, and the aging of the population, the increase in the prevalence of risk factors such as obesity and diabetes and increasing sedentary lifestyles contribute to a rise of the overall incidence of colorectal cancer. Therefore, the development of new therapies for colorectal cancer, notably treatments that prevent early-stage colorectal cancer from evolving into advanced and metastatic stages, would be highly desirable.